Background: Immunological responses to proteins that adhere to ultra-high molecular weight polyethylene have not, to our knowledge, been examined previously in patients who have aseptic loosening. In the current study, polyethylene components from forty-nine failed prostheses recovered during revision procedures were examined for the presence of antibodies that were bound to the polyethylene surface or that were reactive with other proteins that were bound to the polyethylene surface.Methods: The polyethylene components consisted of thirty acetabular cups recovered during revision total hip arthroplasties and nineteen tibial components recovered during revision total knee arthroplasties. After extensive washing, bound proteins were extracted from the polyethylene components with use of 0.1-molar glycine-hydrogen chloride solution followed by four-molar guanidine hydrochloride solution.Results: Sufficient protein for analysis was recovered from forty-two polyethylene components. Polyacrylamide gel electrophoresis demonstrated a minimum of one and a maximum of twelve protein bands, with molecular weights ranging from thirteen to 231 kilodaltons. Immunoblotting revealed the presence of type-I collagen in most (thirty-four) of the forty-two explants, whereas aggrecan proteoglycans were detected in eight samples. Immunoglobulin also was detected in most (thirty-three) extracts, whereas type-II collagen was consistently absent. The presence of autologous antibodies directed against polyethylene-bound proteins in sera drawn at the time of the revision was investigated. Antibodies that were reactive against the ultra-high molecular weight polyethylene-bound proteins were detected in twenty-six of the forty-two patients with use of the Western blot technique. The number of reactive bands ranged from one to six, and the strongest binding was directed against a 103-kilodalton protein. Assays for specificity revealed that these sera autologous antibodies were reactive against the type-I collagen that was present in the explant solutions.Conclusions: We hypothesize that immunoglobulin complexed with polyethylene may fix complement and that the complement cascade may in turn attract inflammatory cells to the polyethylene surface. Our data support the hypothesis that an immunological response to antigens bound to the polyethylene surface may contribute to aseptic loosening.Clinical Relevance: Despite improvements in materials and designs of prostheses, aseptic loosening is the most common complication of total joint replacement, frequently leading to revision operations. We examined the immunological response to proteins that bind to ultra-high molecular weight polyethylene in patients who had aseptic loosening and discovered a high prevalence of antibodies to polyethylene-bound proteins. This immunological response may contribute to an inflammatory reaction in the periprosthetic tissue, ultimately leading to increased bone resorption around the prosthesis.